Why Sanofi's dengue fever vaccine fell short of expectations

In 2015, Sanofi made headlines when it landed approval for the world's first dengue fever vaccine, Dengvaxia, in Mexico. Since then, Dengvaxia has been approved in 16 additional countries in Latin America and Asia — yet its rollout has been plagued by challenges, in part because of the shot's atypical administration requirements and safety concerns raised by independent researchers.

Sanofi spent $1.6 billion over 20 years to develop Dengvaxia, the first vaccine of its kind to target dengue, a mosquito-borne virus that's estimated to infect 390 million people per year, according to the Access to Vaccines Index. But Sanofi fell dramatically short of its 2016 sales estimate of $231 million. Instead, the shot brought in a mere $63.6 million, according to its earnings reports.

But its innovation has also put it in the hot seat, as critics charge that Sanofi's refusal — at least so far — to limit price could become a boondoggle for public health departments.

Last year, Sanofi revealed it would sell three million doses of Dengvaxia to the Philippines at about $23 per dose, a price point that makes its affordability “uncertain,” according to the Access to Vaccines Index. Sanofi's own analysis shows the vaccine is cost-effective for governments. But because Dengvaxia targets multiple age groups, countries must stockpile large quantities upfront.

Broadly, the Dengvaxia story reflects the challenges of being the first-to-market vaccine in middle-income countries. Dengvaxia's rocky rollout may offer valuable insights for Sanofi's competitors — among them Takeda and GlaxoSmithKline. Chiefly, some argue the drug's price was set too high and its administration schedule too burdensome for the governments to manage on their own.

“The bottom line is the vaccine is imperfect,” says Dagna Constenla, Ph.D., associate scientist at Johns Hopkins Bloomberg School of Public Health. “But the bigger concern for people has been that of safety, and that's perhaps why it hasn't rolled out as much as people expected.”

A NEW APPROACH

Many have applauded Sanofi's unique registration strategy of seeking approvals in dengue-endemic markets in Latin America and Asia before seeking approvals in the U.S. and EU. So far, Dengvaxia has been registered in countries including Brazil, Indonesia, Thailand, Singapore, and Argentina.

While the approach has accelerated access to patients who need it most, the strategy has led to confusion among regulators in developing countries, who often look to the FDA and the European Medicines Agency for guidance. In another hang-up, Sanofi has not yet secured approval through the World Health Organization's Prequalification of Medicines Programme, although the shot has been endorsed by the WHO for dengue-endemic regions.

“It's important for vaccines to get prequalified because it gives countries a strong reason to purchase a vaccine,” notes Jayasree Iyer, executive director of the Access to Medicine Foundation. Indeed, a Sanofi spokesperson confirms the company will seek WHO Prequalification.

Dengvaxia is a three-shot vaccine that reduces all four subtypes, or serotypes, of dengue fever, according to results of a Phase III study that enrolled people aged 9 to 16. However, its efficacy varies by subtype, at about 50% for serotype 2, 60% for serotype 1, 70% for serotype 3, and 80% for serotype 4. This amounts to an average efficacy of 65.6%, explains Cesar Mascareñas, Sanofi Pasteur's director of global medical affairs for dengue. Dengvaxia prevented 93% of severe dengue cases and 80% of hospitalizations in the Phase III study.

Safety concerns came to the forefront after a 2016 study published in Science drew attention to the fact that Dengvaxia could make infections worse if used in areas with a very low disease burden. The study reinforced the WHO's conclusion that the shot is more effective among people who have been previously infected and should therefore only be used in regions with a high burden of disease.

Because of the epidemiology of dengue, any vaccination program will require high-quality surveillance data to identify which patients are good candidates. For Dengvaxia, the WHO suggests populations should have 70% seropositivity, meaning a majority of the population has been exposed to the virus.

Collecting this data would be very important before national vaccination programs make a handful of practical decisions, such as how many doses to buy in the future, says Clarke Cole, a researcher at the Access to Medicine Foundation who helped create the group's 2017 Access to Vaccines report. With Dengvaxia, “you have another important factor, which is age. At a higher age, the vaccine performs better,” explains Mascareñas. All of these factors combined make it “very difficult to predict what [the efficacy] will be in a given area.”

For Constenla, the data have been disappointing. “Most of us were thinking the trial would yield pretty favorable results,” she says. “It turned out the vaccine had challenges for efficacy as well as safety.”

REGISTRATION AND ROLLOUT

Dengvaxia's debut has been “different from the rollout of other vaccines in the recent past,” Iyer notes, referencing Sanofi's registration strategy, the peculiar epidemiology of dengue, and the challenges of delivering all three doses of the shot. But despite 17 approvals, only the Philippines and Brazil's Paraná state have incorporated Dengvaxia into government-backed routine immunization programs.

According to the 2017 Access to Vaccines report, Dengvaxia's approval has created an “invaluable” opportunity for companies to develop new rollout strategies that “respond to the contemporary global health challenge.” Because it is only approved in people aged 9 to 45, Sanofi is operating in a “catch-up market,” says Edward Buthusiem, managing director, Berkeley Research Group. Moreover, vaccination isn't mandatory in most countries.

Dengue is also endemic to many middle-income countries that are wealthy enough to be disqualified from international aid from groups such as Gavi, a vaccine program sponsored by the Bill & Melinda Gates Foundation. “Some countries struggle quite a lot with the introduction of new vaccines,” Constenla adds. “It's not that easy to introduce a vaccine outside the scope of a routine vaccine administration program because patients tend not to follow up.”

It's important for vaccine companies to keep in mind that even in middle-income countries, “regulatory agencies don't always happen formally,” Constenla continues. “Sometimes they're ad hoc, or there's a gap in the knowledge base and training and expertise.” This can lead to haphazard vaccine immunization program rollouts.

In terms of Dengvaxia's administration schedule, the closest parallel is the HPV vaccine, which is administered in young adults via a series of shots. According to Mascareñas, many governments are looking to tap into the existing infrastructure for HPV vaccinations, which includes outreach to education departments that have access to teens and preteens.

LOOMING COMPETITION

Sanofi was the first to market with a dengue fever vaccine, but it probably won't be the last. Takeda has a candidate in Phase III testing, with a Phase II interim analysis indicating its vaccine might work against all four serotypes regardless of the patient's prior exposure to the vaccine. GlaxoSmithKline has its own candidate, which is still in preclinical testing.

“In both of these cases, the companies have expressed [they will seek] WHO prequalification, which is an important step so that lower-income countries can access the vaccine,” Cole notes.

In addition to multinational drug companies, independent research groups are moving forward with their own trials. In January, Brazil's Butantan Institute moved into a Phase III trial of TV003, a vaccine licensed from the National Institutes of Health.

If Takeda or GSK emerges with a vaccine that is safer or easier to administer, and is of equal or better efficacy, it won't matter that Dengvaxia was first to market, Buthusiem says. In addition, the safety and efficacy profile of these new vaccines will ultimately be far more important than the price.

In a sense, Sanofi is paving the way for future novel vaccine rollouts. The Dengvaxia story reflects “the difficulties of rolling out a vaccine and how it works in the real world,” Cole explains.

Constenla notes that vaccine companies have a responsibility to help governments strengthen advocacy and network-building, not only for the vaccine, but also for all prevention and control strategies. However, Sanofi sees its own role as more limited.

“Vaccination programs are clearly developed and implemented by countries,” Mascareñas says. “In that sense, we can only support with scientific information in terms of the best way to use the vaccine” and to provide “updated information” on ongoing trials.

Correction: Due to an editing error, an earlier version of this article incorrectly cited potential public health usage of the vaccine to prevent the spread of Zika. The story has been updated.